Signal Pathways

Chemical signal molecules are secreted by cells into the extracellular compartment. This is not a very specific way for these signals to find their targets because substances that diffuse through interstitial fluid or that travel through the blood come in contact with many cells. Yet cells do not respond to every signal that reaches them.

Why do some cells respond to a chemical signal while other cells ignore it? The answer lies in the target cell’s receptor proteins [here]. A cell can respond to a particular chemical signal only if the cell has the appropriate receptor protein to bind that signal (Fig. 6.1d).

If a target cell has the receptor for a signal molecule, binding of the signal molecule to the receptor protein initiates a response. All signal pathways share the following features (Fig. 6.2):

  1. The signal molecule is a ligand that binds to a protein receptor. The ligand is also known as a first messenger because it brings information to the target cell.

  2. Ligand-receptor binding activates the receptor.

  3. The receptor in turn activates one or more intracellular signal molecules.

  4. The last signal molecule in the pathway creates a response by modifying existing proteins or initiating the synthesis of new proteins.

FIG. 6.2 Signal pathways

In the following sections, we describe some basic signal pathways. They may seem complex at first, but they follow patterns that you will encounter over and over as you study the systems of the body. Most physiological processes, from the beating of your heart to learning and memory, use some variation of these pathways. One of the wonders of physiology is the fundamental importance of these signal pathways and the way they have been conserved in animals ranging from worms to humans.

Receptor Proteins Are Located Inside the Cell or on the Cell Membrane

Protein receptors for signal molecules play an important role in physiology and medicine. About half of all drugs currently in use act on receptor proteins. Target cell receptor proteins may be found in the nucleus, in the cytosol, or on the cell membrane as integral proteins. Where a chemical signal binds to its receptor largely depends on whether that signal molecule is lipophilic or lipophobic (Fig. 6.3).

FIG. 6.3 Target cell receptors may be on the cell surface or inside the cell

Lipophilic signal molecules enter cells by simple diffusion through the phospholipid bilayer of the cell membrane [here]. Once inside, they bind to cytosolic receptors or nuclear receptors (Fig. 6.3a). Activation of intracellular receptors often turns on a gene and directs the nucleus to make new mRNA (transcription, [here]). The mRNA then provides a template for synthesis of new proteins (translation, [p. 112]). This process is relatively slow and the cell’s response may not be noticeable for an hour or longer. In some instances, the activated receptor can also turn off, or repress, gene activity. Many lipophilic signal molecules that follow this pattern are hormones.

Lipophobic signal molecules are unable to enter cells by simple diffusion through the cell membrane. Instead, these signal molecules remain in the extracellular fluid and bind to receptor proteins on the cell membrane (Fig. 6.3b). (Some lipophilic signal molecules also bind to cell membrane receptors in addition to their intracellular receptors.) In general, the response time for pathways linked to membrane receptor proteins is very rapid: responses can be seen within milliseconds to minutes.

We can group membrane receptors into four major categories, illustrated in Figure 6.3c. The simplest receptors are chemically gated (ligand-gated) ion channels called receptor-channels [here]. Ligand binding opens or closes the channel and alters ion flow across the membrane.

Three other receptor types are shown in Figure 6.3c: G protein-coupled receptors, receptor-enzymes, and integrin receptors. For all three, information from the signal molecule must be passed across the membrane to initiate an intracellular response. This transmission of information from one side of a membrane to the other using membrane proteins is known as signal transduction. We will take a closer look at basic signal transduction before returning to the four receptor types that participate in it.

Concept Check

  1. List four components of signal pathways.

  2. Name three cellular locations of receptors.

Membrane Proteins Facilitate Signal Transduction

Signal transduction is the process by which an extracellular signal molecule activates a membrane receptor that in turn alters intracellular molecules to create a response. The extracellular signal molecule is the first messenger, and the intracellular molecules form a second messenger system. The term signal transduction comes from the verb to transduce, meaning “to lead across” {trans, across + ducere, to lead}.

A transducer is a device that converts a signal from one form into a different form. For example, the transducer in a radio converts radio waves into sound waves (Fig. 6.4). In biological systems, membrane proteins act as transducers. They convert the message of extracellular signals into intracellular messenger molecules that trigger a response.

FIG. 6.4 Signal transduction

The basic pattern of a biological signal transduction pathway is shown in Figure 6.5 and can be broken down into the following events.

FIG. 6.5 Biological signal transduction

  1. An extracellular signal molecule (the first messenger) binds to and activates a membrane receptor.

  2. The activated membrane receptor turns on its associated proteins and starts an intracellular cascade of second messengers.

  3. The last second messenger in the cascade acts on intracellular targets to create a response.

Figure 6.5b details the intracellular events in basic signal transduction pathways:

  1. Membrane receptors and their associated proteins usually either

    1. (a) activate protein kinases, which are enzymes that transfer a phosphate group from ATP to a protein [here]. Phosphorylation is an important biochemical method of regulating cellular processes.

    2. (b) activate amplifier enzymes that create intracellular second messengers.

  2. Second messenger molecules in turn

    1. (a) alter the gating of ion channels. Opening or closing ion channels creates electrical signals by altering the cell’s membrane potential [here].

    2. (b) increase intracellular calcium. Calcium binding to proteins changes their function, creating a cellular response.

    3. (c) change enzyme activity, especially of protein kinases or protein phosphatases, enzymes that remove a phosphate group. The phosphorylation or dephosphorylation of a protein can change its configuration and create a response.

  3. The proteins modified by calcium binding and phosphorylation are responsible for the cell’s response to the signal. Examples of responses include increased or decreased enzyme activity and opening or closing of gated ion channels.

Cascades

Figure 6.6a shows how the steps of a signal transduction pathway form a cascade. A signaling cascade starts when a stimulus (the signal molecule) converts inactive molecule A (the receptor) to an active form. Active A then converts inactive molecule B into active B, active molecule B in turn converts inactive molecule C into active C, and so on, until at the final step a substrate is converted into a product. Many intracellular signal pathways are cascades. Blood clotting is an important example of an extracellular cascade.

Amplification

In signal transduction pathways, the original signal is not only transformed but also amplified {amplificare, to make larger}. In a radio, the radio wave signal is also amplified. In cells, signal amplification turns one signal molecule into multiple second messenger molecules (Fig.  6.6b).

The process begins when the first messenger ligand combines with its receptor. The receptor-ligand complex turns on an amplifier enzyme. The amplifier enzyme activates several molecules, which in turn each activate several more molecules as the cascade proceeds. By the end of the process, the effects of the ligand have been amplified much more than if there were a 1:1 ratio between each step.

Amplification gives the body “more bang for the buck” by enabling a small amount of ligand to create a large effect. The most common amplifier enzymes and second messengers are listed in the table in Figure 6.6c.

In the sections that follow, we will examine in more detail the four major types of membrane receptors (see Fig. 6.3c). Keep in mind that these receptors may be responding to any of the different kinds of signal molecules—hormones, neurohormones, neurotransmitters, cytokines, or paracrine and autocrine signals.

Concept Check

  1. What are the four steps of signal transduction?

  2. What happens during amplification? In Figure 6.6b, amplification of one signal molecule binding to the receptor results in how many small dark blue intracellular signal molecules?

  3. Why do steroid hormones not require signal transduction and second messengers to exert their action? (Hint: Are steroids lipophobic or lipophilic? [here])

The Most Rapid Signal Pathways Change Ion Flow through Channels

The simplest receptors are ligand-gated ion channels. Most of these receptors are neurotransmitter receptors found in nerve and muscle. The activation of receptor-channels initiates the most rapid intracellular responses of all receptors. When an extracellular ligand binds to the receptor-channel protein, a channel gate opens or closes, altering the cell’s permeability to an ion. Increasing or decreasing ion permeability rapidly changes the cell’s membrane potential [here], creating an electrical signal that alters voltage-sensitive proteins (Fig. 6.7).

FIG. 6.7 Signal transduction using ion channels

One example of a receptor-channel is the acetylcholine-gated monovalent (“one-charge”) cation channel of skeletal muscle. The neurotransmitter acetylcholine released from an adjacent neuron binds to the acetylcholine receptor and opens the channel. Both Na+ and K+ flow through the open channel, K+ leaving the cell and Na+ entering the cell along their electrochemical gradients. The sodium gradient is stronger, however, so net entry of positively charged Na+ depolarizes the cell. In skeletal muscle, this cascade of intracellular events results in muscle contraction.

Receptor-channels are only one of several ways to trigger ion-mediated cell signaling. Some ion channels are linked to G protein-coupled receptors. When a ligand binds to the G protein receptor, the G protein pathway opens or closes the channel.

Finally, some membrane ion channels are not associated with membrane receptors at all. Voltage-gated channels can be opened directly with a change in membrane potential. Mechanically gated channels open with pressure or stretch on the cell membrane [here]. Intracellular molecules, such as cAMP or ATP, can open or close non-receptor-linked ligand-gated channels. The ATP-gated K+ channels of the pancreatic beta cell are an example [Fig. 5.26, here].

Most Signal Transduction Uses G Proteins

The G protein-coupled receptors (GPCRs) are a large and complex family of membrane-spanning proteins that cross the phospholipid bilayer seven times (see Fig. 6.3c are a large and complex family of membrane-spanning proteins that cross the phospholipid bilayer seven times (see ). The cytoplasmic tail of the receptor protein is linked to a three-part membrane transducer molecule known as a G protein. Hundreds of G protein-coupled receptors have been identified, and the list continues to grow. The types of ligands that bind to G protein-coupled receptors include hormones, growth factors, olfactory molecules, visual pigments, and neurotransmitters. In 1994, Alfred G. Gilman and Martin Rodbell received a Nobel Prize for the discovery of G proteins and their role in cell signaling (see http://nobelprize.org/nobel_prizes/medicine/laureates/1994).

G proteins get their name from the fact that they bind guanosine nucleotides [here]. Inactive G proteins are bound to guanosine diphosphate (GDP). Exchanging the GDP for guanosine triphosphate (GTP) activates the G protein. When G proteins are activated, they either (1) open an ion channel in the membrane or (2) alter enzyme activity on the cytoplasmic side of the membrane.

G proteins linked to amplifier enzymes make up the bulk of all known signal transduction mechanisms. The two most common amplifier enzymes for G protein-coupled receptors are adenylyl cyclase and phospholipase C. The pathways for these amplifier enzymes are described next.

Many Lipophobic Hormones Use GPCR-cAMP Pathways

The G protein-coupled adenylyl cyclase-cAMP system was the first identified signal transduction pathway (Fig. 6.8). It was discovered in the 1950s by Earl Sutherland when he was studying the effects of hormones on carbohydrate metabolism. This discovery proved so significant to our understanding of signal transduction that in 1971 Sutherland was awarded a Nobel Prize for his work.

FIG. 6.8 G protein-coupled signal transduction

Figure Questions: Using the pattern shown in Figure 6.6a, create a cascade that includes ATP, cAMP, adenylyl cyclase, a phosphorylated protein, and protein kinase A.

The G protein-coupled adenylyl cyclase-cAMP system is the signal transduction system for many protein hormones. In this system, adenylyl cyclase is the amplifier enzyme that converts ATP to the second messenger molecule cyclic AMP (cAMP). Cyclic AMP then activates protein kinase A (PKA), which in turn phosphorylates other intracellular proteins as part of the signal cascade.

G Protein-Coupled Receptors Also Use Lipid-Derived Second Messengers

Some G protein-coupled receptors are linked to a different amplifier enzyme: phospholipase C (Fig. 6.8b). When a signal molecule activates this G protein-coupled pathway, phospholipase C (PLC) converts a membrane phospholipid (phosphatidylinositol bisphosphate) into two lipid-derived second messenger molecules: diacylglycerol and inositol trisphosphate.

Diacylglycerol (DAG) is a nonpolar diglyceride that remains in the lipid portion of the membrane and interacts with protein kinase C (PKC), a Ca2+-activated enzyme associated with the cytoplasmic face of the cell membrane. PKC phosphorylates cytosolic proteins that continue the signal cascade.

Inositol trisphosphate (IP3) is a water-soluble messenger molecule that leaves the membrane and enters the cytoplasm. There it binds to a calcium channel on the endoplasmic reticulum (ER). IP3 binding opens the Ca2+ channel, allowing Ca2+ to diffuse out of the ER and into the cytosol. Calcium is itself an important signal molecule, as discussed later.

Receptor-Enzymes Have Protein Kinase or Guanylyl Cyclase Activity

Receptor-enzymes have two regions: a receptor region on the extracellular side of the cell membrane, and an enzyme region on the cytoplasmic side (see Fig. 6.3c). In some instances, the receptor region and enzyme region are parts of the same protein molecule. In other cases, the enzyme region is a separate protein.

Ligand binding to the receptor activates the enzyme. The enzymes of receptor-enzymes are either protein kinases, such as tyrosine kinase (Fig. 6.9), or guanylyl cyclase, the amplifier enzyme that converts GTP to cyclic GMP (cGMP) [here]. Because of the association of these receptors with enzymes, they are now grouped into a receptor family called catalytic receptors.

FIG. 6.9 Receptor-enzymes: The tyrosine kinase receptor

Ligands for receptor-enzymes include the hormone insulin as well as many cytokines and growth factors. The insulin receptor protein has its own intrinsic tyrosine kinase activity. In contrast, most cytokine receptor proteins do not have intrinsic enzyme activity. Instead, cytokine binding activates a cytosolic enzyme called Janus family tyrosine kinase, usually abbreviated as JAK kinase.

Integrin Receptors Transfer Information from the Extracellular Matrix

The membrane-spanning proteins called integrins [here] mediate blood clotting, wound repair, cell adhesion and recognition in the immune response, and cell movement during development. On the extracellular side of the membrane, integrin receptors bind either to proteins of the extracellular matrix [here] or to ligands such as antibodies and molecules involved in blood clotting. Inside the cell, integrins attach to the cytoskeleton via anchor proteins (Fig. 6.3c). Ligand binding to the receptor causes integrins to activate intracellular enzymes or alter the organization of the cytoskeleton. Integrin receptors are also classified as catalytic receptors.

The importance of integrin receptors is illustrated by inherited conditions in which the receptor is absent. In one condition, platelets—cell fragments that play a key role in blood clotting—lack an integrin receptor. As a result, blood clotting is defective in these individuals.

Figure 6.10 is a summary map of basic signal transduction, showing the general relationships among first messengers, membrane receptors, second messengers, and cell responses. The modified proteins that control cell responses can be broadly grouped into four categories:

  1. metabolic enzymes

  2. motor proteins for muscle contraction and cytoskeletal movement

  3. proteins that regulate gene activity and protein synthesis

  4. membrane transport and receptor proteins

If you think this list includes almost everything a cell does, you’re right!

Concept Check

  1. Name the four categories of membrane receptors.

  2. What is the difference between a first messenger and a second messenger?

  3. Place the following terms in the correct order for a signal transduction pathway:

    1. (a) cell response, receptor, second messenger, ligand

    2. (b) amplifier enzyme, cell response, phosphorylated protein, protein kinase, second messenger

  4. In each of the following situations, will a cell depolarize or hyperpolarize?

    1. (a) Cl- channel opens

    2. (b) K+ channel opens

    3. (c) Na+ channel opens